Bicyclo 4.4.0 antiviral derivatives

ABSTRACT

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/376,731 filed May 1, 2002.

FIELD OF THE INVENTION

[0002] This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the invention is concerned with new heterocyclicamidopiperazine derivatives that possess unique antiviral activity. Moreparticularly, the present invention relates to compounds useful for thetreatment of HIV and AIDS.

BACKGROUND ART

[0003] HIV-1 (human immunodeficiency virus-1) infection remains a majormedical problem, with an estimated 42 million people infected worldwideat the end of 2002. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million newinfections were reported, and 3.1 million people died from AIDS.Currently available drugs for the treatment of HIV include ninenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations (zidovudine or AZT (or Retrovir®), didanosine (or Videx®),stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (orDDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxilfumarate salt (or Viread®), Combivir® (contains −3TC plus AZT),Trizivir® (contains abacavir, lamivudine, and zidovudine); threenon-nucleoside reverse transcriptase inhibitors: nevirapine (orViramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®),and seven peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, andKaletra® (lopinavir and Ritonavir). Each of these drugs can onlytransiently restrain viral replication if used alone. However, when usedin combination, these drugs have a profound effect on viremia anddisease progression. In fact, significant reductions in death ratesamong AIDS patients have been recently documented as a consequence ofthe widespread application of combination therapy. However, despitethese impressive results, 30 to 50% of patients ultimately failcombination drug therapies. Insufficient drug potency, non-compliance,restricted tissue penetration and drug-specific limitations withincertain cell types (e.g. most nucleoside analogs cannot bephosphorylated in resting cells) may account for the incompletesuppression of sensitive viruses. Furthermore, the high replication rateand rapid turnover of HIV-1 combined with the frequent incorporation ofmutations, leads to the appearance of drug-resistant variants andtreatment failures when sub-optimal drug concentrations are present(Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al;Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)).Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options.

[0004] Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref. 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref 15). A recent overview of non-nucleosidereverse transcriptase inhibitors: perspectives on novel therapeuticcompounds and strategies for the treatment of HIV infection. hasappeared (Buckheit, Robert W., Jr. Expert Opinion on InvestigationalDrugs 2001, 10(8), 1423-1442). A review covering both NRTI and NNRTIshas appeared (Balzarini, J.; De Clercq, E. Antiretroviral Therapy 2001,31-62.). An overview of the current state of the HIV drugs has beenpublished (E. De clercq Journal of Clinical Virology, 2001, 22, 73-89).

[0005] Several indole derivatives including indole-3-sulfones,piperazino indoles, pyrazino indoles, and5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported asHIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1; Williamset al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17; Romero et al,Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20; Silvestri et al,Ref. 21). Indole 2-carboxamides have also been described as inhibitorsof cell adhesion and HIV infection (Boschelli et al, U.S. Pat. No.5,424,329, Ref. 4). Finally, 3-substituted indole natural products(Semicochliodinol A and B, didemethylasterriquinone and isocochliodinol)were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref.22).

[0006] Structurally related aza-indole amide derivatives have beendisclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24;Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC, WO-09611929,Ref. 5(b); Schering Corp., U.S. Pat. No. 0,5023,265, Ref. 5(c)).However, these structures differ from those claimed herein in that theyare aza-indole mono-amide rather than unsymmetrical aza-indolepiperazine diamide derivatives, and there is no mention of the use ofthese compounds for treating viral infections, particularly HIV. Nothingin these references can be construed to disclose or suggest the novelcompounds of this invention and their use to inhibit HIV infection.

REFERENCES CITED

[0007] Patent documents

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[0011] 4. Boschelli, D. H.; Connor, D. T.; Unangst, P. C.Indole-2-carboxamides as inhibitors of cell adhesion. U.S. Pat. No.5,424,329.

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[0013] Other Publications

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SUMMARY OF THE INVENTION

[0101] The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to a virus such as HIV. The compounds of Formula I, whichinclude nontoxic pharmaceutically acceptable salts and/or hydratesthereof, have the formula and meaning as described below. Eachembodiment of a particular aspect of the invention depends from thepreceding embodiment unless otherwise stated.

[0102] A first embodiment of a first aspect of the present invention arecompounds of Formula I, including pharmaceutically acceptable saltsthereof,

[0103] wherein:

[0104] Q is

[0105] A is selected from the group consisting of C₁₋₆alkoxy, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, and heteroaryl; wherein said heteroaryl may bemonocyclic or bicyclic and may be comprised of three to eleven atomsselected from the group consisting of C, N, NR⁹, O, and S, and whereineach ring of said phenyl and heteroaryl is optionally substituted withone to five same or different substituents selected from the groupconsisting of R¹⁹-R²³;

[0106] W is O or —NH;

[0107] T is

[0108] Z¹ is CR¹ or N;

[0109] Z² is CR² or N;

[0110] Z³ is CR³ or N;

[0111] Z⁴ is CR⁴ or N;

[0112] Z⁵ is CR⁵ or N;

[0113] Z⁶ is CR⁶ or N;

[0114] Z⁷ is CR⁷ or N;

[0115] Z⁸ is CR⁸ or N;

[0116] R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independentlyselected from the group consisting of a bond, hydrogen, halogen, cyano,nitro, X′R²⁴, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₄₋₇cycloalkenyl,C₂₋₆alkynyl, aryl, heteroaryl, heteroalicyclic, C(O)NR²⁸R²⁹, COR²⁵ andCO₂R²⁵; wherein said C₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₄₋₇cycloalkenyl, C₂₋₆alkynyl, aryl, heteroaryl, and heteroalicyclic areoptionally substituted with one to nine same or different halogens orfrom one to five same or different substituents selected from thesubstituents comprising group F;

[0117] m, n, and p are each independently 0, 1, or 2 provided that thesum of m, n, and p must equal 1 or 2;

[0118] F is selected from the group consisting of C₁₋₆alkyl, hydroxy,C₁₋₆alkoxy, cyano, halogen, benzyl, N-amido, NR³⁰R³¹,C₁₋₆alkylC(O)NR³⁰R³¹, C(O)NR³⁰R³¹, COOR³², and C₁₋₆alkylCOOR³²;

[0119] R⁹ and R^(9′) are each independently selected from the groupconsisting of hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, andfluoro; or R⁹ and R^(9′) taken together with the carbon atom to whichthey are attached form —C═O, C═S, C═NOR¹⁰, —C═NH, or a 3 or 4 memberedring which may contain up to 1 heteroatom chosen from O, N, S;

[0120] R¹⁰ is hydrogen or C₁₋₆alkyl;

[0121] R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyselected from the group consisting of hydrogen, CH₂F and C₁₋₃alkyl; orone of R¹¹ and R¹², R¹³ and R¹⁴, R¹⁵ and R¹⁶ or R¹⁷ and R¹⁸ takentogether with the carbon atom to which they are attached may form —C═O;

[0122] X′ is selected from the group consisting of NR¹⁰, O, and S;

[0123] R¹⁹, R²⁰, R²¹, R²², and R²³ are each independently selected fromthe group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,halogen, cyano, X′R²⁶, trifluoromethyl, and trifluoromethoxy, whereineach of said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl are optionallysubstituted with one to three same or different substituents selectedfrom halogen and C₁₋₆alkyl;

[0124] R²⁴ is hydrogen or C₁₋₆alkyl;

[0125] R²⁵ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl and heteroaryl;

[0126] R²⁶ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, trifluoromethyl and C(O)R²⁷;

[0127] R²⁷ is selected from the group consisting of C₁₋₆alkyl, NH₂ and—NHC₁₋₃alkyl;

[0128] R²⁸ and R²⁹ are each independently selected from the groupconsisting of hydrogen, SO₂C₁₋₆alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, and heteroalicyclic wherein said C₁₋₆alkyl, C₃₋₇cycloalkyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to nine same or different halogens or C₁₋₆alkyl groups;

[0129] R³⁰ and R³¹ are each independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, wherein saidC₁₋₆alkyl, C₃₋₇cycloalkyl, and aryl are optionally substituted with oneto nine same or different halogens;

[0130] R³² is selected from the group consisting of hydrogen, C₁₋₆alkyl,and C₃₋₇cycloalkyl;

[0131] provided that at any given time only one of the members selectedfrom the group consisting of R¹, R², R^(3,) R⁴, R⁵, R⁶, R⁷ and R⁸ is abond, and further provided that said bond is the point of attachment tothe adjacent carbon atom in the compound of Formula I.

[0132] A second embodiment of the first aspect of the present inventionare compounds of Formula I, including pharmaceutically acceptable saltsthereof, wherein:

[0133] T is

[0134] R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyhydrogen or methyl;

[0135] W is O; and

[0136] A is phenyl or heteroaryl.

[0137] A third embodiment of the first aspect of the present inventionare compounds of Formula I, including pharmaceutically acceptable saltsthereof, wherein:

[0138] R⁹ and R^(9′) are each independently hydrogen or cyano.

[0139] A fourth embodiment of the first aspect of the present inventionwhich depends from the second embodiment, are compounds of Formula I,including pharmaceutically acceptable salts thereof, wherein:

[0140] m is 1; n is 0; and p is 1.

[0141] A fifth embodiment of the first aspect of the present invention,which depends from the second embodiment of the first aspect, arecompounds of Formula I, including pharmaceutically acceptable saltsthereof, wherein:

[0142] m is 1;n is 0; p is 1;

[0143] Q is

[0144] and R⁶ is a bond for point of attachment.

[0145] A sixth embodiment of the first aspect of the present invention,which depends from the fifth embodiment of the first aspect, arecompounds of Formula I, including pharmaceutically acceptable saltsthereof, wherein:

[0146] Q is

[0147] A seventh embodiment of the first aspect of the presentinvention, which depends from the fifth embodiment of the first aspect,are compounds of Formula I, including pharmaceutically acceptable saltsthereof, wherein:

[0148] Q is

[0149] Another embodiment are compounds I wherein

[0150] Q is:

[0151] and R⁶ is a bond for point of attachment.

[0152] Another embodiment are compounds I wherein one of Z₁ through Z₈is N.

[0153] Another embodiment are compounds I wherein two of Z₁ through Z₈is N.

[0154] A first embodiment of the second aspect of the present inventionis a pharmaceutical composition which comprises an antiviral effectiveamount of a compound of Formula I, including pharmaceutically acceptablesalts thereof, as defined in any of the first through sixth embodimentsof the first aspect of the present invention, and one or morepharmaceutically acceptable carriers, excipients or diluents.

[0155] A second embodiment of the second aspect of the present inventionis the pharmaceutical composition of the first embodiment of the secondaspect, useful for treating infection by HIV, which additionallycomprises an antiviral effective amount of an AIDS treatment agentselected from the group consisting of an AIDS antiviral agent; ananti-infective agent; an immunomodulator; and HIV entry inhibitors.

[0156] A first embodiment of a third aspect of the present invention isa method for treating a mammal infected with a virus, comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I, including pharmaceutically acceptable salts thereof, asdefined in any of the first through sixth embodiments of the firstaspect of the present invention, and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

[0157] A second embodiment of a third aspect of the present invention isthe method of the first embodiment of the third aspect, comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I, in combination with an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: an AIDSantiviral agent; an anti-infective agent; an immunomodulator; and an HIVentry inhibitor.

[0158] The third embodiment of a third aspect of the present inventionis the method of either the first or second embodiment of the thirdaspect, wherein said virus is HIV.

DETAILED DESCRIPTION OF THE INVENTION

[0159] Since the compounds of the present invention, may possessasymmetric centers and therefore occur as mixtures of diastereomers andenantiomers, the present invention includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

[0160] “Halogen” refers to chlorine, bromine, iodine or fluorine.

[0161] An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl.

[0162] As used herein, a “heteroaryl” group refers to a monocyclic orfused ring (i.e., rings which share an adjacent pair of atoms) grouphaving in the ring(s) one or more atoms selected from the groupconsisting of nitrogen, oxygen and sulfur and, in addition, having acompletely conjugated pi-electron system. Examples, without limitation,of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl,imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzthiazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl,tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl,isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl,indolyl, isoindolyl, and pyrazinyl.

[0163] As used herein, a “heteroalicyclic” group refers to a monocyclicor fused ring group having in the ring(s) one or more atoms selectedfrom the group consisting of nitrogen, oxygen and sulfur. The rings mayalso have one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl.

[0164] An “alkyl” group refers to a saturated aliphatic hydrocarbonincluding straight chain and branched chain groups. Preferably, thealkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g.,“1-20”, is stated herein, it means that the group, in this case thealkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms,etc. up to and including 20 carbon atoms). More preferably, it is amedium size alkyl having 1 to 10 carbon atoms. For example, the term“C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

[0165] A “cycloalkyl” group refers to a saturated all-carbon monocyclicor fused ring (i.e., rings which share and adjacent pair of carbonatoms) group wherein one or more rings does not have a completelyconjugated pi-electron system. Examples, without limitation, ofcycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, and adamantane.

[0166] A “cycloalkenyl” group refers to an all-carbon monocyclic orfused ring (i.e., rings which share and adjacent pair of carbon atoms)group wherein one or more rings contains one or more carbon-carbondouble bonds but does not have a completely conjugated pi-electronsystem. Examples, without limitation, of cycloalkenyl groups arecyclopentene, cyclohexadiene, and cycloheptatriene.

[0167] An “alkenyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbondouble bond.

[0168] An “alkynyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbontriple bond.

[0169] A “hydroxy” group refers to an —OH group.

[0170] An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkylgroup as defined herein.

[0171] An “O-carboxy” group refers to a R″C(O)O-group, with R″ asdefined herein.

[0172] An “amino” group refers to an —NH₂ group.

[0173] A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x)selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl, and heteroalicyclic and R^(y) selected from hydrogen oralkyl.

[0174] A “cyano” group refers to a —CN group.

[0175] It is known in the art that nitrogen atoms in heteroaryl systemscan be “participating in a heteroaryl ring double bond”, and this refersto the form of double bonds in the two tautomeric structures whichcomprise five-member ring heteroaryl groups. This dictates whethernitrogens can be substituted as well understood by chemists in the art.The disclosure and claims of the present invention are based on theknown general principles of chemical bonding. It is understood that theclaims do not encompass structures known to be unstable or not able toexist based on the literature.

[0176] Physiologically acceptable salts and prodrugs of compoundsdisclosed herein are within the scope of this invention. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

[0177] In the method of the present invention, the term “antiviraleffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,healing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing orameliorating diseases associated with HIV infection.

[0178] The present invention is also directed to combinations of thecompounds with one or more agents useful in the treatment of AIDS. Forexample, the compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure,in combination with effective amounts of the AIDS antivirals,immunomodulators, antiinfectives, or vaccines, such as those in thefollowing table.

Antivirals

[0179] Drug Name Manufacturer Indication 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, (CGP-73547) Novartis AIDS, ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755)Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmuneCMV retinitis Immune globin Cytovene Syntex Sight threateningGanciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-UpjohnHIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266)AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl-inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one,STOCRINE EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FamciclovirSmith Kline herpes zoster, herpes simplex FTC Emory University HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, Roussel AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, PharmaceuticalsAIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection,Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide(Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIVPhosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine ValaciclovirGlaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate salt(Viread ®) AIDS, (reverse transcriptase inhibitor) Combivir ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) abacavir succinateGSK HIV infection, (or Ziagen ®) AIDS, (reverse transcriptase inhibitor)Tenofouir disoproxil Gilead HIV infection, AIDS, (reverse transcriptaseinhibitor)

Immunomodulators

[0180] Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDSBropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs,Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi'sLederle Labs sarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA)FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells GammaInterferon Genentech ARC, in combination w/TNF (tumor necrosis factor)Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz StimulatingFactor Granulocyte Hoechst-Roussel AIDS Macrophage Colony ImmunexStimulating Factor Granulocyte Schering-Plough AIDS, Macrophage Colonycombination Stimulating Factor w/AZT HIV Core Particle RorerSeropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon

Anti-Infectives

[0181] Drug Name Manufacturer Indication Clindamycin with PharmaciaUpjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis,candidiasis Pastille Squibb Corp. Prevention of oral Nystatin Pastillecandidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMedPCP treatment Isethionate (IM & IV) (Rosemont, IL) TrimethoprimAntibacterial Trimethoprim/sulfa Antibacterial Piritrexim BurroughsWellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxisIsethionate for Inhalation Spiramycin Rhone-Poulenc Cryptosporidialdiarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211cryptococcal meningitis Trimetrexate Warner-Lambert PCP DaunorubicinNeXstar, Sequus Kaposi's sarcoma Recombinant Human Ortho Pharm. Corp.Severe anemia Erythropoietin assoc. with AZT therapy Recombinant HumanSerono AIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

[0182] Additionally, the compounds of the invention herein may be usedin combination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in Drugs Of The Future 1999, 24(12), pp. 1355-1362; Cell, Vol.9, pp. 243-246, Oct. 29, 1999; and Drug Discovery Today, Vol. 5, No. 5,May 2000, pp. 183-194.

[0183] It will be understood that the scope of combinations of thecompounds of this invention with AIDS antivirals, immunomodulators,anti-infectives, HIV entry inhibitors or vaccines is not limited to thelist in the above Table, but includes in principle any combination withany pharmaceutical composition useful for the treatment of AIDS.

[0184] Preferred combinations are simultaneous or alternating treatmentsof with a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

[0185] In such combinations the compound of the present invention andother active agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

[0186] The preparative procedures and anti-HIV-1 activity of the novelheterocyclic amidopiperazine derivatives of Formula I are summarizedbelow.

Abbreviations

[0187] The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the invention and the examples. Some ofthe abbreviations used are as follows: h = hour(s) rt = room temperaturemol = mole(s) mmol = millimole(s) g = gram(s) mg = milligram(s) mL =milliliter(s) TFA = Trifluoroacetic Acid DCE = 1,2-Dichloroethane CH₂Cl₂= Dichloromethane TPAP = tetrapropylammonium perruthenate THF =Tetrahydofuran DEPBT =3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one DMAP =4-dimethylaminopyridine P-EDC = Polymer supported1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =N,N-dimethylformamide Hunig's Base = N,N-Diisopropylethylamine mCPBA =meta-Chloroperbenzoic Acid azaindole = 1H-Pyrrolo-pyridine PMB =4-Methoxybenzyl DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone OTf =Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh =1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC =1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide TMS = Trimethylsilyl DCM =Dichloromethane

[0188] Chemistry

[0189] The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. General procedures toconstruct compounds of Formula I and intermediates useful for theirsynthesis are described in the following Schemes.

[0190] Preparation of Compounds of Formula I

[0191] It should be noted that in many cases reactions are depicted foronly one position of an intermediate, such as the R₅ position, forexample. It is to be understood that such reactions could be used atother positions, such as R₁-R₈, of the various intermediates. Reactionconditions and methods given in the specific examples are broadlyapplicable to compounds with other substitution and other tranformationsin this application.

[0192] Two general literature references for some of the chemistrydepicted in Scheme 1 is Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida,H.; Chem Lett. 1983, 859 or Yang; Z.; Zhang, Z.; Meanwell, N. A.; Kadow,J. F.; Wang, T.; Org. Lett. 2002, published in the web edition, hardcopy in press.

[0193] Schemes 1 through 4c describe general reaction schemes forpreparing various compounds of Formula I. While these schemes are verygeneral, other permutations such as carrying a precursor or precursorsto substituents R¹ through R⁷ through the reaction scheme and thenconverting it to a compound of Formula I in the last step are alsocontemplated methods of this invention. Nonlimiting examples of suchstrategies follow in subsequent schemes.

[0194] Scheme 1, and 2 depict a general method suitable for thesynthesis of many of the compounds of formula I. As shown in theseschemes, a suitable protected piperazine derivative, PG-TH, of FormulaVI, (wherein PG is an appropriate amine protecting group) is acylatedwith an appropriate acylating agent, AC(O)L, (wherein L is a suitableleaving group) to provide the protected acylated piperazine derivativeof Formula V. Compound V is then deprotected using standard methods toprovide the acylated piperazine derivative of Formula IV. For example,when PG represents tertiary-butoxycarbonyl the compound of Formula V canbe deprotected to provide a compound of Formula IV by treatment with astrong acid, such as trifluoroacetic acid or hydrochloric acid, in anappropriate solvent such as dichloromethane. Alternatively, when PGrepresents benzyl the deprotection may be effected by hydrogenation. Theacylpiperazine derivative of Formula IV is then alkylated with2-chloroacetonitrile in the presence of an appropriate base, such astriethylamine, 4-methylmorpholine or diisopropylethyl amine in anappropriate solvent, such as THF, to provide the cyanomethylacylpiperazine derivative of Formula III. Reaction of a heterocyclicderivative of formula II (wherein L is an appropriate leaving group,such as OCH₃) with an anion of the cyanomethyl acylpiperizine of FormulaIII, provides cyanomethyl amide derivative of Formula Ia. Oxidation ofthe cyanomethyl amide derivative of Formula Ia to a ketoamide derivativeof Formula Ib is carried out preferentially using a peracid such asmeta-chloroperoxybenzoic acid (mCPBA). The cheap and simple oxidantsodium hypochlorite solution (common bleach) is also useful.

[0195] Other peracids could also be utilized for the oxidation of acompound of Formula Ia to a compound of Formula Ib, including peroxyacetic acid generated in situ. Other methods for oxidation are shown inthe following Table A which describes a one pot condensation/oxidationprocess which is usually preferred: TABLE A Oxidation Conditions

Oxidation Conditions mCPBA (1 eq.) mCPBA (1.5 eq.) mCPBA (2 eq.) Oxone(2 eq., with H₂O) H₂O₂ (2 eq., 30% in H₂O) H₂O₂-Urea (2 eq.) AcOOH (2eq., 32% in AcOH) Clorox ™ (2 eq., 5.25% NaOCl)

[0196] Compounds of Formula II can be esters, preferably methyl esters,however other simple alkyl esters or activated acid derivatives such asacid chlorides, acid anhydrides, or Weinreb amides could also findutility in preparing compounds as shown.

[0197] Scheme 2 depicts a general method suitable for the synthesis ofmany of the compounds of Formula I using the methodology described forScheme 1. As shown in Scheme 1, a piperazine derivative of formula IVmay be alkylated with chloroacetonitrile in the presence of a suitablebase, such as triethylamine, in an appropriate aprotic solvent, such astetrahydrofuran, to provide a cyanomethylpiperazine derivative offormula III. Other tertiary amine bases such as 4-methylmorpholine mayalso be used in this step. Reaction of a suitable heterocycliccarboxylate ester of formula II with an anion of a cyanomethylpiperazine derivative provides cyanomethyl esters of formula Ia. Theanion of the cyanomethyl piperazine derivative can be generated bytreating a solution of the cyanomethyl piperazine derivative with anappropriate base, such as sodium hexamethyldisilazide (NaHMDS). Theesters of formula II are preferably methyl esters but other simple alkylesters or activated acid derivatives such as acid chlorides, acidanhydrides, or Weinreb amides could also find utility. Thus, forexample, L in Scheme 1 can be OR′, where R′ is C₁₋₆ alkyl, with methylpreferred. Oxidation of the alpha cyano ketone of Formula Ia to aketoamide of Formula Ib is carried out using a peracid oxidant such asmeta-chloroperoxybenzoic acid. Other peracids may be useful for theoxidation of Ia to Ib, including peroxy acetic acid generated in situ.In addition other preferred methods such as bleach were described above.

[0198] Alternatively, as shown in Scheme 3 below, compounds of formulaIb can be prepared by reaction of a heterocyclic glyoxylic acidderivative of Formula VII (QC(O)CO₂H), with a piperazine derivative ofFormula IV (HTC(O)A), under standard peptide coupling conditions toprovide compounds of Formula Ib. Standard peptide coupling refers tocoupling an amine with a carboxylic acid in the presence of an amineacid coupling reagent such as DCC, PyBop, EDC, or DEPBT. The preparationof DEPBT is described by Li, H.; Jiang, X.; Ye, Y. -H.; Fan, C.; Romoff,T.; and Goodman, M. in Organic Lett., 1999, 1, 91-93.

[0199] One preferred method for carrying out this reaction is to use thereagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT)and an amine HTC(O)A in DMF as solvent containing a tertiary amine suchas diisopropylethylamine. Another preferred method is to use the reagent1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in anappropriate solvent and in the presence of diisopropylethylamine.Typical stoichiometries are given in the specific examples but theseratios may be modified. The amide bond construction reactions depictedin Scheme 3 could be carried out using the specialized conditionsdescribed herein or alternatively by applying the conditions or couplingreagents for amide bond construction described in the literature. Somespecific non-limiting examples are given in this application.

[0200] Another method for the synthesis of compounds of Formula Ib isshown in Scheme 4, below. The hydrolysis of the heterocyclic oxoaceticacid ester intermediate of Formula VIII, to form the heterocyclicoxoacetic acid of Formula VII, is shown in Step 1 of Scheme 4. The usualconditions employ methanolic or ethanolic sodium hydroxide followed byacidification with aqueous hydrochloric acid of varying molarity but 1MHCl is preferred. Lithium hydroxide or potassium hydroxide could also beemployed and varying amounts of water could be added to the alcohols.Propanols or butanols could also be used as solvents. Elevatedtemperatures up to the boiling points of the solvents may be utilized ifambient temperatures do not suffice. Alternatively, the hydrolysis maybe carried out in a non polar solvent such as CH₂Cl₂ or THF in thepresence of Triton B. Temperatures of −70° C. to the boiling point ofthe solvent may be employed but −10° C. is preferred. Other conditionsfor ester hydrolysis are well known to chemists of average skill in theart. It is to be understood that these hydrolysis conditions areapplicable to other regioisomeric heterocyclic oxoacetic acid esters.The glyoxylic acid derivative of Formula VII may then be converted to acompound of Formula Ib directly as described in Scheme 3, above.Alternatively, as Step 2 of Scheme 4 depicts, the glyoxylic acidderivative of Formula VII can be converted to the correspondingglyoxylic acid chloride of Formula IX. This transformation can becarried out using thionyl chloride, reaction with oxalyl chloride, orother methods well known in the art. Alternatively, the intermediates ofFormula IX can also be obtained as described hereinafter for Scheme1-29. Coupling of the piperazine derivative, H-T-C(O)A to theintermediate glyoxylic acid chloride of Formula IX, may be carried outin a basic solvent such as pyridine or triethylamine, or in an inertsolvent in the presence of pyridine as base or other tertiary aminebases to provide compounds of Formula Ib. Schotten-Baumann conditionscould also be employed for this coupling (aqueous base).

[0201] Synthesis of Intermediates

[0202] It should be noted that in many cases reactions are depicted foronly one position of an intermediate or compound of Formula I, such asthe R⁶ position, for example. It is to be understood that such reactionscould be used at other positions, such as R¹-R⁴ or R⁷ of the variousintermediates or compounds of Formula I. Reaction conditions and methodsgiven in the specific examples are broadly applicable to compounds withother substitution and to other tranformations in this application.

[0203] Heterocyclic carboxylates of general formula QC(O)OR (such asthose of formula Ia in Scheme 1, herein) or suitable surrogates may bepurchased from commercial sources or synthesized. Bicyclo 4.4.0heteroaromatic rings which by definition contain fused aromatic ringsare well known in the art. Examples include such compounds asquinolines, isoquinolines, fused pyrimidines etc. Searching scifinderfor such compounds produces numerous examples of such substituted andunsubstituted compounds. Some additional examples of pertinentliterature are listed below:

[0204] Compounds of formula IIa can be prepared by two basic strategiesusing numerous methods from the literature or the methods within thisapplication. Strategy 1 involves the synthesis of the appropriatecompound containing a carboxylate ester while strategy 2 involves thesynthesis of the precursor followed by installation of a carboxylateester moiety. These methods are described in the literature referencesabove or other art.

[0205] If desired, the substituents R¹ through R⁸ may be prepared toform either halide, triflate, cyano, carboxaldehyde, carboxylic acid, orcarboxylic ester. These groups can be transformed into other compoundsof claim 1 using the known methodology for such substituents and somedescribed below.

[0206] Katritzky, Alan R.; Rees, Charles W.; Comprehensive heterocyclicchemistry: the structure, reactions, synthesis, and uses of heterocycliccompounds 1^(st) ed.Oxford (Oxfordshire) ; New York: Pergamon Press,1984. 8 v.

[0207] Katritzky, Alan R., Rees, Charles W. , Scriven, Eric F. V.Comprehensive heterocyclic chemistry II: a review of the literature1982-1995.

[0208] Comprehensive heterocyclic chemistry II: a review of theliterature 1982-1995: the structure, reactions, synthesis, and uses ofheterocyclic compounds 1st ed Oxford; New York: Pergamon, 1996. 11 v. in12: ill.;

[0209] “Isoquinolines” New York, Wiley, 1981-1995; v. 1-3, Series:Chemistry of heterocyclic compounds; v. 38;

[0210] Alternate Authors: Grethe, Guenter.

[0211] “An Interscience-publication.” Pt. 2 edited by F. G. Kathawala,Gary M. Coppola, Herbert F. Schuster. Pt. 3 edited by Gary M. Coppola,Herbert F. Schuster.

[0212] The fused bicyclic 4.4.0 aromatic or heteroaromatic carboxylatesof formula IIa can be prepared by two basic strategies using numerousmethods from the literature or the methods within this application. Thefirst strategy involves the synthesis of an appropriate fused bicyclicaromatic or heteroaromatic ring containing a carboxylate ester groupwhile the second strategy involves the synthesis of the parentheterocycle followed by installation of a carboxylate ester moiety ontothe parent ring system. The following Schemes I-1 through I-28 representvarious heterocyclic carboxylates which may serve as usefulintermediates for the preparation of compounds of Formula I. The methodsused to prepare compounds of Formula I from the intermediates are thosedescribed for Schemes 1 through 4c.

[0213] Schemes I-1 through I-28 depict methods and conditions for thesynthesis of intermediate carboxylates according to the first strategywherein a fused bicyclic containing carboxylate moiety is synthesized.Literature references follow the depicted Schemes.

[0214] General Procedures for the Preparation of [6,6] Bicyclic Systems:

[0215] The following procedures are examples which can be used toprepare the substituents which form Q or suitable precursors. Note, inSchemes I-1 to I-28, R₃-R₈ means R¹, R², R³ and R⁸ corresponding toCompounds I; L of Scheme 1 corresponds to OR′; and R₇-R₆ corresponds toR⁶ and R⁷ in corresponding Compounds I. Also, subscripted R groups (e.g.R₆) corresponds to the superscripted R group (e.g. R⁶) in compounds ofFormula I.

[0216] A. Procedures to Make Substituted Isoquinilines

[0217] Boger, D. L.; Chen, J. H.; J Org Chem 1995, 60 (22), 7369.

[0218] Kende, A. S.; Ebetino, F. H.; Tetrahedron Lett 1984, 25 (9), 923.

[0219] Ried, W.; Berg, A.; Schmidt, G.; Chem Ber 1952, 85, 204.

[0220] Borsche, W.; Noll, W.; Justus Liebigs Ann Chem 1937, 532, 127.

[0221] This could be extended to other series with additional nitrogensin the rings:

[0222] Ferranti, A.; Garuti, L.; Giovanninetti, G.; Roberti, M.; Varoli,L.; Farmaco, Ed Sci 1993, 48 (11), 1547-1553.

[0223] Author Not Provided; Synth Commun 1986, 2, 157.

[0224] Campbell, K. N.; Helbing, C. H.; Kerwin, J. F.; J Am Chem Soc1946, 68, 1840.

[0225] Spivey, A. M.; Curd, F. H. S.; J Chem Soc 1949, 2656.

[0226] Fieser, L. F.; Brown, R. H.; J Am Chem Soc 1949, 71, 3609.

[0227] Mattox, V. R.; Kendall, E. C.; J Biol Chem 1951, 188, 287.

[0228] Phillips, A. P.; Maggiolo, A.; J Am Chem Soc 1952, 74, 3922.

[0229] Roth, R.; Erlenmeyer, H.; Helv Chim Acta 1954, 37, 1064.

[0230] This could be extended to:

[0231] Shiba, S. A.; Indian J Chem, Sect B 1995, 34 (10), 895-896.

[0232] MIYASHITA, A.; KAWASHIMA, T.; IIJIMA, C.; HIGASHINO, T.;

[0233] Heterocycles 1992, 33 (1), 211-218.

[0234] Kobayashi, Y.; Kumadaki, I.; Taguchi, S.; Chem Pharm Bull 1969,17, 2335.

[0235] Kaneko, C.; Ochiai, E.; et al.; Chem Pharm Bull 1960, 8, 487.

[0236] Feely, W. E.; Beavers, E. M.; J Am Chem Soc 1959, 81, 4004.

[0237] Org Synth 1962, 42, 30.

[0238] This could be extended to:

[0239] Boger, D. L.; Panek, J. S.; J Am Chem Soc [JACSAT] 1985, 107(20), 5745.

[0240] This could be extended to:

[0241] Henn, L.; Hickey, D. M. B.; Moody, C. J.; Rees, C. W.; J ChemSoc, Perkin Trans 1 [JCPRB4] 1984, 2189.

[0242] Gilchrist, T. L.; Rees, C. W.; Rodrigues, J. A. R.; J Chem Soc,Chem Commun [JCCCAT] 1979, 627.

[0243] Hickey, D. M. B.; Moody, C. J.; Rees, C. W.; J Chem Soc, ChemCommun [JCCCAT] 1982, 1 (14), 3.

[0244] This could be extended to:

[0245] D'A. ROCHA GONSALVES, A. M.; PINHO E MELO, T. M. V. D.;

[0246] GILCHRIST, T. L.; Tetrahedron 1992, 48 (33), 6821-6826.

[0247] This could be extended to:

[0248] In Schemes I-13 and I-14, R″ is methyl or ethyl.

[0249] SINGH, S. K.; DEKHANE, M.; LE HYARIC, M.; POTIER, P.; DODD, R.H.; Heterocycles 1997, 44 (1), 379-391.

[0250] This could be extended to:

[0251] Kepez, M.; Monatsh Chem 1989, 120, 127.

[0252] Keller-Schierlein, W.; Prelog, V.; Helv Chim Acta 1957, 40, 205.

[0253] This could be extended to:

[0254] XR═R where R⁶═OR²⁴, NR¹⁰R²⁴, SR²⁴, H.

[0255] Begland, R. W.; Hartter, D. R.; J Org Chem [JOCEAH] 1972, 37,4136.

[0256] Monge, A.; Palop, J. A.; Pinol, A.; Martinez-Crespo, F. J.;Narro, S.; Gonzalez, M.; Sainz, Y.; Lopez De Cerain, A.; Hamilton, E.;Barker, A. J.; J Heterocycl Chem [JHTCAD] 1994, 31 (5), 1135-1139.

[0257] Monge, A.; Palop, J. A.; Del Castillo, J. C.; Caldero, J. M.;Roca, J.; Romero, G.; Del Rio, J.; Lasheras, B.; J Med Chem [JMCMAR]1993, 36 (19), 2745-2750.

[0258] MAHGOUB, S. A.; Phosphorus, Sulfur Silicon Relat Elem [PSSLEC]1991, 61, 151-160.

[0259] This could be extended to:

[0260] RAO, P. S.; VENKATARATNAM, R. V.; Indian J Chem, Sect B [IJSBDB]1992, 31 (11), 733-735.

[0261] This could be extended to:

[0262] ANZINI, M.; CAPPELLI, A.; VOMERO, S.; GIORGI, G.; LANGER, T.;BRUNI, G.; ROMEO, M. R.; BASILE, A. S.; J Med Chem [JMCMAR] 1996, 39(21), 4275-4284.

[0263] Adams, D.; Dominguez, J.; Lo Russo, V.; De Rekowski, N. M.; GazzChim Ital [GCITA9] 1989, 119 (5), 281.

[0264] Adams, D. R.; Dominguez, J. N.; Perez, J. A.; Tetrahedron Lett[TELEAY] 1983, 24, 517.

[0265] Alonso, M. A.; Del Mar Blanco, M.; Avendano, C.; Menendez, J. C.;Heterocycles [HTCYAM] 1993, 36 (10), 2315-2325.

[0266] This could be extended to:

[0267] X═R , where R⁷═H, OR²⁴, NR¹⁰R²⁴

[0268] Merour, J. Y.; Tatibouet, F.; Synthesis [SYNTBF] 1978, 698.

[0269] Lutz, R. E.; et al.; J Am Chem Soc [JACSAT] 1946, 68, 1285.

[0270] J Org Chem [JOCEAH] 1950, 15, 317.

[0271] J Org Chem [JOCEAH] 1950, 15, 326.

[0272] Ind Eng Chem Prod Res Dev [IEPRA6] 1950, 42, 1565.

[0273] de Diesbach, H.; Gross, J.; Tschamen, W.; Helv Chim Acta [HCACAV]1951, 34, 1050.

[0274] Borsche, W.; Doeller, W.; Wagner-Roemmich, M.; Ber Dtsch Chem Ges[BDCGAS] 1943, 76, 1099.

[0275] Chem Abstr [CHABA8], 1944 (4947)

[0276] Baumgarten, H. E.; Saylor, J. L.; J Am Chem Soc [JACSAT] 1957,79, 1502.

[0277] This could be extended to:

[0278] X═R⁷, where R⁷═H, OR²⁴, NR¹⁰R²⁴

[0279] Gazit, A.; Levitzki, A.; et al.; J Med Chem [JMCMAR] 1996, 39(11), 2170.

[0280] This could be extended to:

[0281] X═R⁵, where R⁵═OR²⁴, NR¹⁰R²⁴, SR²⁴, H

[0282] Rupe, H.; Heckendorn, A.; Helv Chim Acta [HCACAV] 1926, 9, 980.

[0283] Ukraintsev, I. V.; Taran, S. G.; Gorokhova, O. V.; Marusenko, N.A.; Kovalenko, S. N.; Turov, A. V.; Filimonova, N. I.; Ivkov, S. M.;Khim Geterotsikl Soedin [KGSSAQ] 1995 (2), 195-203.

[0284] Lab Bellon SA Roger; France Patent 1994, 2703681 (FR-2703681),94-326370.

[0285] Alonso, M. A.; Del Mar Blanco, M.; Avendano, C.; Menendez, J. C.;Heterocycles [HTCYAM] 1993, 36 (10), 2315-2325.

[0286] RAO, K. R.; BHANUMATHI, N.; SATTUR, P. B.; J Heterocycl Chem[JHTCAD] 1991, 28 (5), 1339-1340.

[0287] This could be extended to:

[0288] X═R⁵, where R⁵═OR²⁴, NR¹⁰R²⁴, SR²⁴, H

[0289] The following references contain preparations or references topreparations of the quinoline acid above. The hydroxy group may bederivatized to an ether or converted to a triflate which may beconverted to cyano using palladium/copper catalyzed couplings or thetriflate may be coupled directly to heterocyclic or aromatic stannanes.

[0290] References for above:

[0291] Yabe et. al. JP 10087489A2

[0292] Yabe et. al. PCT W09628423

[0293] Portlock et. al U.S. Pat. No. 4,461,896A

[0294] Wright et. al. DE3004370

[0295] Scheme 1-29 shows the preparation of glyoxylic acid chloridederivatives which are also useful intermediates for the preparation ofcompounds of Formula I. The glyoxylic acid chloride derivative offormula QC(O)C(O)Cl can be prepared by treating an appropriateheterocycle of formula Q-H with oxalyl chloride in an appropriatesolvent such as diethyl ether in the presence of an appropriate Lewisacid catalyst such as aluminum trichloride The glyoxylic acid chloridederivatives can then be reacted with an appropriately substitutedpiperazine derivative of formula H-TC(O)A in an appropriate solvent suchas tetrahydrofuran or acetonitrile in the presence of a suitable basesuch as diisopropylethylamine or pyridine to provide compounds offormula I. Additional methodology for attaching the —C(O)C(O)TC(O)Amoiety to an appropriate heterocycle is described in WO-0076521published by the World Patent Office on 12/21/00.

[0296] An alternate method (three step procedure) for preparingcompounds of Formula I is shown in Scheme 1-30, below. Reaction of aknown or synthesized heterocyclic acetic acid derivative of Formula XYZ1with a piperazine derivative of Formula IV, under standard peptidecoupling conditions will afford the desired amides of Formula Im.Preferred peptide coupling conditions include the use of EDC in thepresence of diisopropylethylamine. Treatment of the amide derivative,Ie, with a strong base, such as lithium diisopropylamide (LDA), followedby quenching with (+,−)-Davis' reagent will afford the correspondingα-hydroxyamide derivatives of formula If. Finally, oxidation of theα-hydroxyamide of Formula If, with an oxidant, such as Dess-Martinreagent, will provide the desired α-ketoamides of formula Ib.

[0297] An alternative route which may be used to obtain the(x-ketoamides of Formula Ib involves the direct oxidation of theacetamide derivative of Formula Im. A preferred method is to treat theacetamide derivative of Formula Ie with an oxidant, such as seleniumdioxide (SeO₂) in a polar solvent such as dioxane to provide the desiredcc-ketoamides of formula Ib.

[0298] It will be appreciated by one skilled in the art that certainfunctional groups present on the heterocyclic moiety represented by thevariable Q of a compound of Formula I or its precursor may be convertedto other groups by transformations known in the art. Schemes 6-9 providenonlimiting examples of transformations useful to provide variouscompounds of Formula I. In Schemes 6-9 various functional grouptransformations are shown for substituents of the heterocyclic moietyrepresented by Q in the general formula (with the point of attachmentbeing at one of positions R¹-R⁸). In these schemes, Q′ represents theportion of Q which together with the indicated substitutent makes up Q.It is to be understood that the functional group conversions may beapplicable to any of the R¹-R⁸ positions of the heterocyclic moiety(other than the R¹-R⁸ position which is the point of attachment). Thetransformations depicted in Schemes 6-9 are applicable to bothintermediates which can then be converted to compounds of Formula I andto compounds of Formula I.

[0299] Scheme 6, above, depicts the conversion of a bromide to variousother functional groups. In equation 1, treatment of the bromide with astrong base, such as n-butyl lithium, in an aprotic solvent, such asTHF, followed by treatment with dimethylformamide results in thealdehyde shown.

[0300] Equation 2 of Scheme 6 depicts the conversion of the bromide tothe cyano derivative. This transformation can be achieved by treatingthe bromide with a reagent such as sodium cyanide, copper cyanide orzinc cyanide in a solvent such as dimethylformamide.

[0301] Equations 3 and 4 of Scheme 6 show a suitable bromo derivativemay undergo metal mediated couplings with various stannanes or boronicacid derivatives. Conditions for the Stille-type coupling, shown inequation 3, are well known in the art and involve treatment of thebromide (or iodide or triflate) with an aryl, heteroaryl or vinylstannane in the presence of an appropriate palladium catalyst in anappropriate solvent. Palladium catalysts used include, but are notlimited to, tetrakis-triphenylphosphine palladium and palladium (II)acetate. Appropriate solvents include, but are not limited to, polarsolvents such as dioxane and 1-methyl-2-pyrrolidinone. Numerous examplesof conditions for carrying out the Stille reaction may be found inreferences such as Farina, V.; Roth G. P.; Adv. Met.-Org. Chem. 1996, 5,1-53; Farina, V.; Krishnamurthy, V.; Scott, W. J.; Org. React. (N.Y.)1997, 50, 1-652; and Stille, J. K.; Angew. Chem. Int. Ed. Engl. 1986,25, 508-524.

[0302] Equation 4 of Scheme 6 depicts the Suzuki-type coupling of thebromide with an appropriate boronic acid derivative. Appropriate boronicacid derivatives include aryl and heteroaryl boronic acid derivatives.This transformation may be carried out in the presence of an appropriatepalladium catalyst, such as tetrakis-triphenylphosphine palladium, and abase, such as potassium carbonate, in a solvent or solvent mixture suchas dimethylformamide and water. Typical reaction conditions for carryingout the Suzuki-type reaction can be found in Miyaura, N.; Suzuki, A.;Chem. Rev. 1995, 95, 2457.

[0303] Alternative methods are available to one skilled in the art forcarrying out transformations analogous to those shown in equations 3 and4 of Scheme 6. For example, substituted azabenzoxazoles or otherheterocyclic groups of general formula Q containing a chloride, bromide,iodide, triflate, or phosphonate undergo coupling reactions with aboronate (Suzuki type reactions) or a stannane to provide thecorresponding substituted heterocycles. Triflates and boronates areprepared via standard literature procedures from the correspondinghydroxy bearing heterocycle. The substituted heterocyles may undergometal mediated coupling to provide compounds of Formula I wherein thedesired substituent is aryl, heteroaryl, or heteroalicyclic for example.The bromoheterocycle intermediates, (or heterocyclic triflates oriodides) may undergo Stille-type coupling with heteroarylstannanes asshown in equation 3. Conditions for this reaction are well known in theart and the following are three example references a) Farina, V.; Roth,G. P. Recent advances in the Stille reaction; Adv. Met.-Org. Chem. 1996,5, 1-53. b) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stillereaction; Org. React. (N. Y.) 1997, 50, 1-652. and c) Stille, J. K.Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524. Other references forgeneral coupling conditions are also in the reference by Richard C.Larock Comprehensive Organic Transformations 2nd Ed. 1999, John Wileyand Sons New York. All of these references provide numerous conditionsat the disposal of those skilled in the art to carry out transformationssuch as those depicted in equation 3 and 4 of Scheme 6. It can be wellrecognized that a heterocyclic stannane could also be coupled to aheterocyclic or aryl halide or triflate to construct compounds ofFormula I. Suzuki coupling (Norio Miyaura and Akiro Suzuki Chem Rev.1995, 95, 2457.) between a bromo heterocycle intermediate and a suitableboronate could also be employed.

[0304] Suzuki couplings between chloroheterocycle intermediates, asdepicted in equation 5 of Scheme 6, are also feasible. If standardconditions fail new specialized catalysts and conditions can beemployed. Some references (and the references therein) describingcatalysts which are useful for coupling with aryl and heteroarylchlorides are: Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,122(17), 4020-4028; Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999,40(3), 439-442; Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59(17),5034-7; Buchwald, S.; Old, D. W.; Wolfe, J. P.; Palucki, M.; Kamikawa,K.; Chieffi, A.; Sadighi, J. P.; Singer, R. A.; Ahman, J PCT Int. Appl.WO 0002887 2000; Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.1999, 38(23), 3415; Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald,S. L. J. Am. Chem. Soc. 1999, 121(41), 9550-9561; Wolfe, J. P.;Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16), 2413-2416; Bracher,F.; Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; and Bracher,F.; Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.

[0305] Alternatively, the boronate or stannane may be formed on theheterocyclic moiety via methods known in the art and the couplingperformed in the reverse manner with aryl or heteroaryl based halogensor triflates.

[0306] Methods for direct addition of aryl or heteroaryl organometallicreagents to alpha chloro nitrogen containing heterocyles or the N-oxidesof nitrogen containing heterocycles are known and applicable to thecompounds described herein. Some examples are Shiotani et. al. J.Heterocyclic Chem. 1997, 34(3), 901-907; Fourmigue et.al. J.Org. Chem.1991, 56(16), 4858-4864.

[0307] Scheme 7, below, depicts various transformations of a carboxylicacid group with the R⁶ position being used for illustrative purposes. Inequation 1, the carboxylic acid group is being converted to an amide byusing standard peptide coupling techniques. Standard peptide couplingrefers to coupling an amine with a carboxylic acid in the presence of anamine acid coupling reagent such as DCC, PyBop, EDC, or DEPBT.

[0308] Equation 2 of Scheme 7 shows the conversion of the carboxylicacid group to an acylsulfonamide group by treating the carboxylic acidwith a primary sulfonamide, such as methylsulfonamide orphenylsulfonamide in the presence of a peptide coupling agent, such asEDC, and a base, such as DMAP, in an appropriate aprotic solvent, suchas dichloromethane.

[0309] The carboxylic acid group can also be converted to thecorresponding acid chloride by treatment with thionyl chloride (neat orin an inert solvent) or oxalyl chloride in an inert solvent such asbenzene, toluene, THF or dichloromethane as shown in equation 3 ofScheme 7. The acid chloride may then be further reacted, for examplewith an excess of ammonia, primary amine or secondary amine in an inertsolvent such as benzene, toluene, THF or dichloromethane to provide thecorresponding amides. The acid chloride may also be reacted with astoichiometric amount of amine in the presence of a base, such astriethylamine, 4-methylmorpholine, 2,6-lutidine or pyridine.Alternatively, the acid chloride may be reacted with an amine underbasic conditions (usually sodium hydroxide or potassium hydroxide) insolvent mixtures containing water and possibly a miscible cosolvent suchas dioxane or THF.

[0310] The carboxylic acid group can also be esterified, as shown inequation 4 of Scheme 7, using standard conditions well known in the art.For example, the acid may be converted to the methyl ester by treatmentwith diazomethane or trimethylsilyldiazomethane in methanol/benzene.Other standard esterification conditions, such as those described byRichard C. Larock in Comprehensive Organic Transformations 2^(nd) Ed.1999, John Wiley and Sons, New York or Theodora W. Greene and Peter G.M. Wuts in Protective Groups in Organic Synthesis 3^(rd) Ed. 1999,Wiley, New York may also be used.

[0311] Equation 5 of Scheme 7 shows the acid being used as a versatileprecursor for the formation of various heterocycles. The acid could beconverted to hydrazonyl bromide and then a pyrazole via methodsdescribed by Shawali in J. Heterocyclic Chem. 1976, 13, 989. One methodfor general heterocycle synthesis would be to convert the acid to analpha bromo ketone by conversion to the acid chloride using standardmethods, reaction with diazomethane, and finally reaction with HBr. Thealpha bromo ketone could be used to prepare many different compounds ofFormula I as it can be converted to many heterocycles or other compoundsof Formula I. Alpha amino ketones can be prepared by displacement of thebromide with amines. Alternatively, the alpha bromo ketone could be usedto prepare heterocycles not available directly from the aldeheyde oracid. For example, using the conditions described by Hulton et al. inSynth. Comm. 1979, 9, 789 to react the alpha bromo ketone would provideoxazoles. Reaction of the alpha bromoketone with urea via the methodsdescribed by Pattanayak, B. K. et al. in Indian J. Chem. 1978, 16, 1030would provide 2-amino oxazoles. The alpha bromoketone could also be usedto generate furans using beta keto esters as described in ChemischeBerichte 1902, 35, 1545 and Chemische Bericte 1911, 44, 493; pyrroles(from beta dicarbonyls as in Indian J. Chem. 1973, 11, 1260; thiazolesby Hantsch methods as described by Roomi et al in Can. J. Chem. 1970,48, 1689; or isoxazoles and imidazoles as described by Sorrel, T. N. inJ. Org. Chem. 1994, 59, 1589. Coupling of the aforementioned acidchloride with N-methyl-O-methyl hydroxyl amine would provide a “WeinrebAmide” which could be used to react with alkyl lithiums or Grignardreagents to generate ketones. Reaction of the Weinreb anion with adianion of a hydroxyl amine would generate isoxazoles as in Nitz, T. J.et al. J. Org. Chem. 1994, 59, 5828-5832. Reaction with an acetyleniclithium or other carbanion would generate alkynyl indole ketones.Reaction of this alkynyl intermediate with diazomethane or other diazocompounds would give pyrazoles as in Bowden, K. et al. J. Chem. Soc.1946, 953. Reaction with azide or hydroxyl amine would give heterocyclesafter elimination of water. Nitrile oxides would react with the alkynylketone to give isoxazoles as described in Chimichi, S. Synth. Comm.1992, 22, 2909. Reaction of the initial acid to provide an acid chlorideusing for example oxalyl chloride or thionyl chloride or triphenylphosphine/carbon tetrachloride provides a useful intermediate as notedabove. Reaction of the acid chloride with an alpha ester substitutedisocyanide and base would give 2-substituted oxazoles as described byScholkopf et al. in Angew. Int. Ed. Engl. 1971, 10(5), 333. These couldbe converted to amines, alcohols, or halides using standard reductionsor Hoffman/Curtius type rearrangements.

[0312] Equation 1 of Scheme 8 depicts the oxidation of an heterocyclicaldehyde to the corresponding carboxylic acid. Numerous methods aresuitable for the conversion of an aldehyde to an acid and many of theseare well known in the art and described in standard organic chemistrytexts such as Richard C. Larock in Comprehensive Organic Transformations2^(nd) Ed. 1999, John Wiley and Sons, New York. One preferred method isthe use of silver nitrate or silver oxide in aqueous or anhydrousmethanol at a temperature of about 25° C. or as high as reflux for 1 to48 hours. Alternatively, the aldehyde could be oxidized to the acidusing other standard oxidants such as KMnO₄ or CrO₃/H₂SO₄.

[0313] Equation 2 of Scheme 8 depicts the reaction of the aldehyde withhydroxylamine (R═H) in a suitable solvent, such as ethanol to providethe oximes shown.

[0314] Equation 3 of Scheme 8 shows the conversion of the aldehyde groupto an oxazole by using TOSMIC in the presence of potassium carbonate inmethanol. The aldehyde could also be reacted with a metal reagent (R²⁵M)or Grignard reagent (R²⁵MgX, X=halide) to generate secondary alcoholswhich could then be oxidized to the corresponding ketones as shown inequation 4 of Scheme 8. Suitable Grignard reagents would includereagents wherein R²⁵ is alkyl, aryl or heteroaryl. The oxidation of thesecondary alcohols to the corresponding ketones, shown as the secondstep in equation 4, may be accomplished using oxidants such as TPAP,MnO₂ or PCC.

[0315] Equation 1 of Scheme 9 depicts the hydrolysis of a nitrile groupto the corresponding carboxylic acid. Suitable conditions for carryingout this hydrolysis employ heating the nitrile at reflux with potassiumhydroxide in a mixture of water and ethanol for 1 to 100 hours toprovide the acid.

[0316] Equation 2 of Scheme 9 depicts the conversion of the nitrile to atetrazole by reacting the nitrile with ammonium chloride and sodiumazide in DMF. The tetrazole can then be alkylated by treatment with anelectrophile, such as an alkyl halide in the presence of potassiumcarbonate or alternatively by treatment with a reagent such astrimethylsilyldiazomethane in methanol/benzene.

[0317] Scheme 9, equation 3 shows the preparation of an oxadiazole fromthe nitrile by the addition of hydroxylamine followed by ring closureupon treatment with phosgene. The oxadiazole may then be methylatedusing trimethylsilyldiazomethane (TMSCHN₂) in a mixture of methanol andbenzene.

Experimental Procedures

[0318] The following examples represent typical syntheses of thecompounds of Formula I as described generally above. These examples areillustrative only and are not intended to limit the invention in anyway. The reagents and starting materials are readily available to one ofordinary skill in the art.

[0319] Chemistry

[0320] Typical Procedures and Characterization of Selected Examples:

[0321] Unless otherwise stated, solvents and reagents were used directlyas obtained from commercial sources, and reactions were performed undera nitrogen atmosphere. Flash chromatography was conducted on Silica gel60 (0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δ TMS=0. The following internalreferences were used for the residual protons in the following solvents:CDCl₃ (δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50).Standard acronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode. LC/MS Method (i.e., compound identification) ColumnA: YMC ODS-A S7 3.0 × 50 mm column Column B: PHX-LUNA C18 4.6 × 30 mmColumn Column C: XTERRA ms C18 4.6 × 30 mm column Column D: YMC ODS-AC18 4.6 × 30 mm column Column E: YMC ODS-A C18 4.6 × 33 mm column ColumnF: YMC C18 S5 4.6 × 50 mm column Column G: XTERRA C18 S7 3.0 × 50 mmcolumn Column H: YMC C18 S5 4.6 × 33 mm column Column I: YMC ODS-A C18S7 3.0 × 50 mm column Column J: Xterra MS C18 5 um 4.6 × 30 mm columnGradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent BGradient time:  2 minutes Hold time:  1 minute Flow rate:  5 mL/minDetector Wavelength: 220 nm Solvent A:  10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid Solvent B:  10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid

[0322] Compounds purified by preparative HPLC were diluted in methanol(1.2 mL) and purified using the following methods on a Shimadzu LC-10Aautomated preparative HPLC system.

[0323] Preparative HPLC Method (i.e., Compound Purification)

[0324] Purification Method: Initial gradient (40% B, 60% A) ramp tofinal gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100%B, 0% A) Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid SolventB: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid Column: YMC C18 S5 20 ×100 mm column Detector Wavelength: 220 nm

[0325] Preparation of Intermediates is Described Below withCharacterization Data Provided in Tables 1A-1E

[0326] To a solution of tert-butyl-1-piperazinecarboxylate (15.0 g. 80.5mmol) and benzoic acid (8.94 g, 73.2 mmol) in CH₂Cl₂ (500 mL), was addedDMAP (9.84 g, 80.5 mmol) and EDC (15.39 g, 80.5 mmol). The reactionmixture was stirred at rt for 17 h, and then washed with excesshydrochloric acid (5×250 mL, 1 N aq.) and water (350 mL). The organiclayer was dried over MgSO₄, filtered and the filtrate concentrated invacuo to provide Preparation 1 as an off white solid (21 g, 99%). ¹HNMR: (300 MHz, CD₃OD) δ7.46 (m, 5H), 3.80−3.30 (b m, 8H), 1.47 (s, 9H);LC/MS: (ES+) m/z (M+H)⁺=291, (2M+H)⁺=581, HPLC R_(t)=1.430.

[0327] To Preparation 1 was charged a solution of HCl in Dioxane (80 mL,4 M), and the mixture stirred at room temperature for 5 h. The reactionmixture was concentrated in vacuo to afford the hydrochloride salt ofPreparation 2 as a white solid (100% conversion). ¹H NMR: (300 MHz,CD₃OD) δ7.5 (m, 5H), 4.0−3.7 (b, 4H), 3.7−3.6 (b m, 4H); LC/MS: (ES+)m/z (M+H)⁺=191, (2M+H)⁺=381, HPLC R_(t)=0.210.

[0328] Prepared in the same manner as Preparations 1 and 2 starting fromtert-butyl-1-(2-(R)-methylpiperazine)carboxylate (15.0 g. 80.5 mmol) andbenzoic acid (8.94 g, 73.2 mmol). ¹H NMR: (300 MHz, CD₃OD) δ7.47 (m,5H), 4.50 (app d, J=10.6, 1H), 3.59 (b s, 1H), 3.14−2.57(b m, 5H),1.15−0.97 (b m, 3H); LC/MS: (ES+) m/z (M+H)⁺=205, (2M+H)⁺=409, HPLCR_(t)=0.310.

Preparations 4-5

[0329] Preparations 4 and 5 were prepared according to the followinggeneral procedure and as further described below.

[0330] General Procedures:

[0331] Typical procedure to prepare 1-carbonyl-4-cyanomethylpiperazinederivatives: An excess of chloroacetonitrile (7 mL) was added to asolution of piperazine derivative of formula HTC(O)A (10.5 mmol) in THF(100 mL) and Et₃N (10 mL). The reaction was stirred for 10 hours thenwas quenched with saturated aqueous NaHCO₃ (100 mL). The aqueous phasewas extracted with EtOAc (3×100 mL). The combined organic layer wasdried over MgSO₄, filtered, and the filtrate concentrated to a residue,which was used in the further reactions without any purification.

[0332] An excess of chloroacetonitrile (7 mL) was added in to a solutionof 1-benzoylpiperazine (2 g, 10.5 mmol) in THF (100 mL) and Et₃N (10mL). The reaction was stirred for 10 h before being quenched withsaturated aqueous NaHCO₃ (100 mL). The aqueous phase was extracted withEtOAc (3×100 mL). The combined organic layer was dried over MgSO₄ andconcentrated to a residue, Preparation 4, which was used in the furtherreactions without any purification.

[0333] Characterization of Compounds which were Prepared via the SameMethod Described Above Shown in Table 1A: TABLE 1A MS (M + H)⁺ MS (M +H)⁺ Observ. Entry # Structure Calcd. And Retention Time Preparation 4

230.13 230.02 0.84 min (column I) Preparation 5

244.14 244.09 0.96 min (column I)  Preparation 5a (same method as Prep 4and 5)

244.14 244.09 0.95 min (column I)

Preparation 5

[0334]

[0335] An excess of chloroacetonitrile (7 mL) was added in to a solutionof 1-benzoyl-3-(R)-piperazine (2 g, 10.5 mmol) in THF (100 mL) and Et₃N(10 mL). The reaction was stirred for 10 h before being quenched withsaturated aqueous NaHCO₃ (100 mL). The aqueous phase was extracted withEtOAc (3×100 mL). The combined organic layer was dried over MgSO₄ andconcentrated to a residue, Preparation 5, which was used in the furtherreactions without any purification.

[0336] Preparation of Quinoline N-Oxide:

[0337] Typical procedure to prepare quinoline N-oxide from quinoline:Preparation of 5-hydroxylquinoline N-oxide: mCPBA (172 mg) was addedinto a solution of 5-hydroxyl-quinoline (72.6 mg) in EtOAc (10 ml) atroom temperature. After the reaction was stirred at room temperature for12 hours, a precipitate was formed and collected through filtration toafford 77.5 mg of 5-hydroxylquinoline N-oxide. MS m/z: (M+H)⁺ calcd forC₉H₈NO₂ 162.06, found 162.02. HPLC retention time: 0.69 minutes (columnI).

[0338] Characterization of Compounds which were Prepared via the SameMethod Described Above Shown in Table 1B: TABLE 1B MS (M + H)⁺ Entry MS(M + H)⁺ Observ. And # Structure Calcd. Retention Time NO-01

223.97 223.85 1.07 min (column I) NO-02

162.06 162.02 0.56 min (column I)

[0339] Preparation of Quinoline Nitrile from N-Oxide:

[0340] Typical procedure to prepare 2-cyanoquinoline from N-oxide:Preparation of 2-cyano-5-hydroxyl-2-quinoline: Trimethylsilyl cyanide(12.4 ml) was added into a solution of 5-hydroxyl-quinoline N-oxide (5g) with triethylamine (13 ml) in MeCN. After the reaction was stirred atroom temperature for 12 hours, solvents were removed under vaccum toprovide a residue which was then partitioned between saturated NaHCO₃solution (100 ml) and EtOAc (100 ml). The aqueous solution was thenextracted with EtOAc (2×100 ml). And the combined organic layer wasdried over anhydrous MgSO₄, filtered and concentrated to afford a crudeproduct which purified by silica gel column chromatography to provide5.3 g of 2-cyano-5-hydroxylquinoline. MS m/z: (M+H)⁺ calcd for C₁₀H₇N₂O171.06, found 171.03. HPLC retention time: 1.22 minutes (column I).

[0341] Characterization of Compounds which were Prepared via the SameMethod Described Above Shown in Table 1C: TABLE 1C MS MS (M + H)⁺ Entry(M + H)⁺ Observ. And # Structure Calcd. Retention Time CN-01

185.07 184.92 1.39 min (column I) CN-02

171.06 171.03 1.17 min (column I) CN-03

232.97 232.92 1.52 min (column I)

[0342] Preparation of Quinoline Acid via Hydrolysis of Nitrile:

[0343] Typical procedure to prepare quinoline acidfrom nitrile:Preparation of 5-hydroxyl-2-quinoline carboxylic acid:2-cyano-5-hydroxylquinoline (5 g) was added into a mixed solution of 10NNaOH (150 ml) and MeOH (400 ml). After heated at 100° C. for two hours,MeOH was removed under vaccum to give an aqueous solution. When the pHof the solution was adjusted to 5 by using 10N HCl, a yellow solidprecipated out from the solution to afford 4.61 g of5-hydroxyl-2-quinoline carboxylic acid. MS m/z: (M+H)⁺ calcd forC₁₀H₈NO₃ 190.05, found 190.03. HPLC retention time: 0.56 minutes (columnI)

[0344] Preparation of Quinoline Acid via Oxidation of Methyl Group:

[0345] Typical procedure to prepare quinoline carboxylic acid viaoxidation: Preparation of 6-fluoro-2-quinoline carboxylic acid: Air wasbubbled into a solution of 6-fluoro-2-methylquinoline (1 g) with anexcess of t-BuOK (20 ml, 1.0M in t-BuOH) in DMSO. When solvents werealmost all evaporated, water (20 ml) was added to the residue and pH wasadjusted to 7 by adding 10N HCl solution. The aqueous solution was thenextracted with EtOAc (3×20 ml). And the combined organic layer was driedover anhydrous MgSO₄, filtered and concentrated to afford a crudeproduct which purified by silica gel column chromatography to provide1.18 g of 6-fluoro-2-quinoline carboxylic acid. MS m/z: (M+H)⁺ calcd forC₁₀H₇FNO₂ 192.05, found 192.04. HPLC retention time: 1.04 minutes(column I).

[0346] Characterization of Compounds which were Prepared via the SameMethods Described Above Shown in Table 1D: TABLE 1D MS MS (M + H)⁺ Entry(M + H)⁺ Observ. And # Structure Calcd. Retention Time Acid- 01

204.07 204.03 0.91 min (column I) Acid- 02

251.97 251.92 1.32 min (column I) Acid- 03

190.05 190.01 0.45 min (column I)

[0347] Preparation of Quinoline Ester from Acid:

[0348] Typical procedure to prepare quinoline esterfrom acid:Preparation of methyl 5-hydroxyl-2-quinoline carboxylate and methyl5-methoxy-2-quinoline carboxylate: Trimethylsilyldiazomethane (0.61 ml,2.0M in hexane) was added into a solution of 5-hydroxyl-2-quinolinecarboxylic acid (100 ml) in benzene (5 ml) and MeOH (5 ml). After twohours, solvents were removed under vaccum to give a residue, which waspartitioned between saturated NaHCO3 (10 ml) and EtOAc (10 ml). Theaqueous layer was further extracted with EtOAc (2×10 ml). The combinedorganic layer was dried over anhydrous MgSO₄, filtered and concentratedto afford a mixture of two products which purified by silica gel thinlayer chromatography to provide 31.4 mg of methyl 5-hydroxyl-2-quinolinecarboxylate [MS m/z: (M+Na)⁺ calcd for C₁₁H₉NNaO₃ 226.05, found 225.99.HPLC retention time: 1.19 minutes (column I)] and 24.9 mg of of methyl5-methoxy-2-quinoline carboxylate [MS m/z: (M+Na)⁺ calcd for C₁₂H₁NnaO₃240.06, found 239.98. HPLC retention time: 1.51 minutes (column I)].

[0349] Characterization of Compounds which were Prepared via the SameMethod Described Above Shown in Table 1E: TABLE 1E MS MS (M + H)⁺ Entry(M + H)⁺ Observ. And # Structure Calcd. Retention Time Ester- 01

218.08 218.01 1.91 min (column I) Ester- 02

204.07 204.00 1.07 min (column I) Ester- 03

228.04 (M + Na)⁺ 227.97 (M + Na)⁺1.41 min (column I) Ester- 04

265.98 265.94 1.57 min (column I)

[0350] Typical Procedures and Characterization of Selected Examples ofCompounds of Formula I with Characterization Data Provided in Tables 2-6and Biological Data Provided in Tables 7-9:

[0351] General Procedures in Scheme 1:

[0352] Typical procedure to prepare intermediate1-benzyl-4-cyanomethylpiperazines: Preparation of1-benzyl-4-cyanomethylpiperazine: An excess of chloroacetonitrile (7 ml)was added in to a solution of benzylpiperazine (2 g, 10.5 mmol) in THF(100 ml) and Et₃N (10 ml). The reaction was stirred for 10 hours beforequenched with saturated aqueous NaHCO₃ (100 ml). The aqueous phase wasextracted with EtOAc (3×100 ml). The combined organic layer was driedover MgSO₄ and concentrated to a residue, which was used in the furtherreactions without any purification.

[0353] Compounds which were Prepared via the same Method Described AboveShown in Table 2A: TABLE 2A MS (M + MS (M + H)⁺ Entry H)⁺ Observ. And #Structure Calcd. Retention Time SM- 01

230.13 230.02 0.84 min (column I) SM- 02

244.14 244.09 0.96 min (column I) SM- 03

244.14 244.09 0.95 min (column I)

[0354]

[0355] Typical procedure to prepare final Compound I, cyano-ketone:Preparation ofN-(benzoyl)-N′-[2-(quinolin-2-yl)-2-oxo-1-cyano-ethyl]-piperazine:NaHMDS )1.75 ml, 1M in THF) was added into a solution of1-benzyl-4-cyanomethylpiperazin (100 mg) and methylquinoline-2-carboxylate (82 mg) in THF. The reaction was stirred for 10hours. After solvents were removed under vaccum, the residue waspurified using Shimadzu automated preparative HPLC System to giveN-(benzoyl)-N′-[2-(quinolin-2-yl)-2-oxo-l1-cyano-ethyl]-piperazine (10mg).

[0356] Typical procedure to prepare final Compound I,oxoacety-piperazines: Preparation ofN-(benzoyl)-N′-[(quinolin-2-yl)-2-oxoacetyl]-piperazine: NaHMDS (1.75ml, 1M in THF) was added into a solution of1-benzyl-4-cyanomethylpiperazin (100 mg) and methylquinoline-2-carboxylate (82 mg) in THF. After the reaction was stirredfor 10 hours, mCPBA (200 mg, >77%) was added and the resulted mixturewas stirred for another 10 hours. Then solvents were removed undervaccum, the residue was purified using Shimadzu automated preparativeHPLC System to giveN-(benzoyl)-N′-[(quinolin-2-yl)-2-oxoacetyl]-piperazine (1.4 mg). TABLE2 Characterization of Compounds of Formula I with the FollowingSubstructure:

MS (M + H)⁺ Entry MS (M + H)⁺ Observ. And # Q R Calcd. Retention Time 16

H 385.17 385.19 1.42 min. (Column A) 15

Me 399.18 399.10 1.44 min. (Column A) 18

(R)-Me 399.18 399.09 1.45 min. (Column A) 21

(S)-Me 399.18 399.08 1.45 min. (Column A) 17

H 385.17 385.09 1.22 min. (Column A) 19

®-Me 400.18 400.07 1.43 min. (Column A) 23

(S)-Me 400.18 400.08 1.42 min. (Column A) 40

H 386.16 386.09 1.20 min (Column I) 20

®-Me 400.18 400.09 1.11 min. (Column A) 22

(S)-Me 400.18 400.09 1.11 min. (Column A) 24

H 529.15 528.96 1.01 min. (column A) 26

Me 415.18 415.05 1.50 min (column I) 25

Me 477.09 476.87 1.85 min (column I) 29

Me 429.19 429.25 1.58 min (column I) 27

Me 499.16 499.26 1.181 min (column I) 40

(R)-Me 476.10 476.00 2.01 min (colunm J) 41

(R)-Me 456.19 456.11 1.86 min (column J)

[0357] TABLE 3 Characterization of Compounds of Formula I with theFollowing Substructure:

MS (M + H)⁺ Entry MS (M + H)⁺ Observ. And # Q R Calcd. Retention Time 1

H 374.15 374.07 1.27 min. (Column A) 5

Me 388.17 388.06 1.33 min. (Column A) 6

(R)-Me 388.17 388.10 1.33 min. (Column A) 9

(S)-Me 388.17 388.10 1.34 min. (Column A) 14

H 375.15 375.16 1.17 min. (Column A) 2

H 375.15 375.08 1.18 min. (Column A) 7

(R)-Me 389.16 389.09 1.24 min. (Column A) 11

(S)-Me 389.16 389.09 1.24 min. (Column A) 3

H 374.15 374.08 1.21 min. (Column A) 8

(R)-Me 388.17 388.10 1.28 min. (Column A) 12

(S)-Me 388.17 388.10 1.27 min. (Column A) 4

H 375.15 375.13 0.96 min. (Column A) 13

(S)-Me 389.16 389.08 1.03 min. (Column A) 33

Me 418.18 418.26 1.45 min (column I) 34

Me 406.16 406.09 1.39 min (column I) 38

Me 418.18 418.21 1.51 min (column I) 37

Me 404.16 404.02 1.30 min (column I) 35

Me 466.08 465.81 1.66 min (column I) 36

Me 404.16 403.95 1.41 min (column I) 39

H 374.15 374.09 1.14 min (column I) 28

Me 488.14 488.00 1.58 min (column I) 42

(R)-Me 465.08 466.97 1.81 min (column J) 43

(R)-Me 445.18 445.08 1.67 min (column J) 44

(R)-Me 431.16 431.06 1.55 min (column J)

[0358]

[0359] Preparation of(R)-N-benzoyl-N′-(2-cyano-acetyl)-2-methylpiperazine: DCC (2.43 g) andtriethylamine (5 ml) were added into a solution of cyanoacetic acid (1g) and (R)-N-benzoyl-N′-methylpiperazine (2.84 g) in THF (50 ml). Afterreaction stirred at room temperature for 12 hours, solvents were removedunder vaccum to give a residue which was purified by silica gel columnchromatography to afford 3 g of(R)-N-benzoyl-N′-(2-cyano-acetyl)-3-methylpiperazine. MS m/z: (M+H)⁺calcd for C₁₅H₁₈N₃O₂ 272.14, found 272.17. HPLC retention time: 0.93minutes (column H).

[0360] Preparation of N-benzoyl-N′-(2-cyano-acetyl)piperazine:N-benzoyl-N′-(2-cyano-acetyl)piperazine was prepared by the same methodfor of (R)-N-benzoyl-N′-(2-cyano-acetyl)-3-methylpiperazine. MS m/z:(M+H)⁺ calcd for C₁₄H₁₆N₃O₂ 258.12, found 258.15. HPLC retention time:0.83 minutes (column H).

[0361] Typical procedure to prepare oxoacety-piperazines: Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(3-chloro-quinoxalin-2-yl)-2-oxoacetyl]-piperazine:NaHMDS (1.53 ml, 1M in THF) was added into a solution of(R)-N-benzoyl-N′-(2-cyano-acetyl)-3-methylpiperazine (215 mg) and2,3-dichloroquinoxaline (100 mg) in THF (10 ml). After the reaction wasstirred for 10 hours, LC-MS showed the formation of(R)-N-(benzoyl)-3-methyl-N′-[(3-chloro-quinoxalin-2-yl)-2-cyanoacetyl]-piperazine,[MS m/z: (M+H)⁺ calcd for C₂₃H₂₁ClN₅O₂ 434.14, found 434.12. HPLCretention time: 1.59 minutes (column H)]. Then, acetic peracid (4 ml,25% in acetic acid) was added and the resulted mixture was stirred foranother 1 hour to show the formation of(R)-N-(benzoyl)-3-methyl-N′-[(3-chloro-quinoxalin-2-yl)-2-oxoacetyl]-piperazine,[MS m/z: (M+H)⁺ calcd for C₂₂H₂₀ClN₄O₃ 423.12, found 423.06. HPLCretention time: 1.67 minutes (column H)].

[0362] General Procedures in Scheme 4b:

[0363] Typical procedure to prepare cyano-ketone: Preparation ofN-(benzoyl)-N′-[2-(5-hydroxyl-quinolin-2-yl)-2-imino-1-cyano-ethyl]-piperazine:NaHMDS (1.75 ml, 1M in THF) was added into a solution of1-benzyl-4-cyanomethylpiperazin (88.2 mg) and2-cyano-5-hydroxylquinoline (62 mg) in THF. The reaction was stirred for10 hours. After solvents were removed under vaccum, the residue waspurified using Shimadzu automated preparative HPLC System to giveN-(benzoyl)-N′-[2-(5-hydroxyl-quinolin-2-yl)-2-imino-1-cyano-ethyl]-piperazine(2.6 mg). TABLE 4 Characterization of Compounds of Formula I with theFollowing Substructure:

MS Obsd. And Example Q R¹⁵ MS Cald. Retention Time 32

Me 414.19 413.96 1.40 min (column I) 30

Me 414.19 414.15 1.30 min (column I) 31

Me 428.21 428.16 1.49 min (column I)

[0364] Chemistry Experimental Section B

[0365] Indole Replacements

[0366] Some examples could be prepared by reaction of glyoxylic acid(QCOCOOH) with a piperidine or substitutued piperidine hydrochloride inthe presence of EDC (Scheme 10).

EXAMPLE PREPARATION

[0367]

[0368] To a solution of glyoxylic acid (QCOCOOH, 1 equiv.) in DMF wasadded (R)-methylbenzoyl piperazine hydrochloride (1.5 equiv), followedby EDC (1.5 equiv.) and I-Pr2NEt (3 equiv). The reaction mixture wasstirred at room temperature for 16h and the crude product was purifiedby prep. HPLC. The compounds were characterized as shown above.

[0369] (Q₂ is Q-C(O)—

for Table 3 and Q₂ is Q-C(O)—CH(CN)—

for Table 2 in compounds of Formula I)

[0370] Examples 1-12 (Table 3) and Example 15-16 (Table 2) are preparedby reaction of commercially available carboxylic acids and benzoylpiperazine in the presence of EDC and catalytic1-hydroxy-4-azabenzotriazole (Scheme 11).

[0371] Example 54 (Table 8) is prepared by reaction of naphthaleneglyoxamide A with neat DAST at 60° C. (Scheme 12).

[0372] Example 55 is prepared in a three step procedure as shown inScheme 13. Reaction of 2-napthylacetonitrile with LDA followed byquenching with 1,2-dibromoethane affords the desiredα-cyclopropylnitrile. Hydrolysis then yields the corresponding acidwhich is then coupled with (R)-methylbenzoyl piperazine to afford thedesired cyclopropyl derivative 55.

General Procedure for the Preparation of Examples 42-53 in Table 5

[0373]

[0374] To commercially available carboxylic acid QCOOH (1 equiv.) in DMFwas added benzoylpiperazine (1 equiv), 1-hydroxy-4-azabenzotriazole (0.2equiv) followed by EDC (1 equiv) and i-Pr₂NEt (2 equiv). The reactionmixture was stirred at room temperature for 16 h. The crude productswere then purified by prep HPLC and were characterized as shown in Table5.

Procedure for the Preparation of Example 59

[0375] Step A

[0376] To α-hydroxyamide B (prepared as described above usingcommercially available naphthylglycolic acid) was added CH₂Cl₂ followedby Dess-Martin Periodinane (1.5 equiv.). The reaction mixture wasstirred at room temperature for 4 h. The mixture was diluted with CH₂Cl₂and was washed with water and brine, dried over MgSO4, filtered andconcentrated. The crude product was purified by flash chromatography(0-50% EtOAc/Hexane) to yield the desired glyoxamide (HPLC retentiontime: 1.45 min. MS: 387 (M+H)⁺).

[0377] To the naphthalene glyoxamide C above (15 mg) was added DAST (250uL). The reaction mixture was stirred at room temperature for 1 h andwas then heated to 60° C. for 16 h. The reaction was quenched with MeOHand the crude product was purified by prep. HPLC to yield the desiredα-difluoroamide.

[0378] Procedure for the Preparation of example 55

[0379] To 2-naphthylacetonitrile (167 mg, 1 mmol) in THF (5 mL) at −78°C. was added LDA (3.5 equiv). The reaction mixture was stirred for 30min before the addition of 1,2-dibromoethane (375 mg, 2 equiv.). Themixture was then allowed to warm to room temperature and was stirred atrt for 16 h. The reaction was quenched with NH4Cl (aq) and was dilutedwith CH2Cl2. The organic phase was washed with water, 0.1 M HCl andbrine, dried over MgSO4, filtered and concentrated. The product was thenpurified by flash chromatography (0-30% EtOAc/Hexane).

[0380] To cyclopropylamide shown above (70 mg) in EtOH/H20 (9:1, 10 mL)was added KOH (200 mg). The reaction mixture was then heated to refluxfor 16 h. The reaction was then quenched with 1M HCl and the crudeproduct was purified by prep. HPLC.

[0381] To cyclopropyl acid shown above (20 mg), (R)-methylpiperazinehydrochloride (27 mg) and EDC (28 mg) was added1-hydroxy-7-azabenzotriazole (3 mg) followed by DMF (1 mL). The reactionmixture was stirred at room temperature for 16 h, and the crude productwas purified by prep. HPLC. TABLE 5

HPLC Example Retention MS Data # AZ R¹⁵ Time (M + H)⁺ 42

H 1.44 359 43

Me 1.22 373 44

H 1.48 359 45

Me 1.23 373 46

Me 1.38 389 47

Me 1.38 389 48

(R)-Me 1.56 417 49

H 1.45 389 50

(R)-Me 1.44 403 51

H 1.47 401 52

(R)-Me 1.52 415 53

(R)-Me 1.59 403 54

(R)-Me 1.62 409 55

(R)-Me 1.67 399

[0382] Chemistry Experimental Section C

[0383] A Method for Preparing the Compounds of Formula I via Coupling ofan Acetic Acid Derivative Followed by Appropriate Functionalization isDescribed.

[0384] Examples 56-59 in (Table 6) were prepared in a three stepprocedure (Scheme 15). Reaction of commercially available 1- or2-naphthalene acetic acid with benzoyl piperazine in the presence of EDCafforded the desired amides. Treatment with LDA followed by quenchingwith (+,−)-Davis' reagent afforded the corresponding α-hydroxyamides.Finally, oxidation with Dess-Martin reagent yielded the desiredα-ketoamides.

General Procedure for the Preparation of Examples 56-59 in Table 6

[0385]

[0386] To 1- or 2-naphthalene acetic acid (2 mmol) in DMF (2 mL) wasadded benzoylpiperazine (2 mmol) followed by EDC (2.1 mmol). Thereaction was stirred at room temperature for 16 h. The crude product wasdiluted with CH2Cl2 and was washed with HCl (0.1 M), water and brine.The organic phase was dried over MgSO4, filtered and concentrated. Thecrude product was purified by flash chromatgraphy (0-50% EtOAc/Hexane)to afford the desired amides.

[0387] To naphthalene acetamide D prepared above (0.1 mmol) in THF (2mL) was added (+,−)-Davis Reagent (0.1 mmol). The reaction mixture wascooled to −78° C. before LDA (200 uL, 1M in THF) was added. The mixturewas stirred at −78° C. for 2 h and was then quenched with sat. NH4Cl.The solution was diluted with CH2Cl2 and was washed with 0.1M HCl, waterand brine. The organic phase was dried over MgSO4, filtered andconcentrated. The crude product was then purified by flashchromatography (0-60% EtOAc/Hexane) to afford the desireα-hydroxyamides.

[0388] To α-hydroxyamide (1 equiv) in CH2Cl2 was added Dess-MartinPeriodinane (2 equiv.). The reaction mixture was stirred at roomtemperature for 16 h and the crude product was then purified by prep.HPLC to afford the desired α-keto amide. The products were characterizedas shown in Table 6. TABLE 6

HPLC Example Retention MS Data # BZ R¹⁵ Time (M + H)⁺ 56

H 1.54 373 57

H 1.54 373 58

Me 1.47 387 59

(R)-Me 1.45 387

Preparation of Compounds of Formula I

[0389] General Procedure to Prepare cyano-ketone Derivatives:

[0390] NaHMDS (1.75 mL, 1.0 M in THF) was added into a solution of anamido cyanomethylpiperazine derivative of formula AC(O)TCH₂CN (0.44mmol) and carboxylate of formula QC(O)OR′ (R′ is methyl or ethyl, 0.44mmol) in THF. The reaction was stirred for 10 hours at room temperaturethen was concentrated in vacuo. The residue was purified using Shimadzuautomated preparative HPLC System to give the product of general formulaQC(O)CH(CN)TC(O)A.

[0391] General Procedure to Prepare Oxoacetylpiperazine Derivatives:

[0392] General procedure to prepare oxoacetyl-piperazines: NaHMDS (1.75mL, 1.0 M in THF) was added into a solution of an appropriatecyanomethylpiperazine derivative of formula AC(O)TCH₂CN, (0.44 mmol),and an appropriate heterocyclic carboxylate of formula QCO₂R′, where R′is methyl or ethyl, (0.44 mmol) in an appropriate solvent such as THF.After the reaction was stirred for hours at room temperature, mCPBA (200mg, >77%) was added and the resulting mixture was stirred for another 10hours at room temperature. Then the reaction mixture was concentrated invacuo and the residue was purified using Shimadzu automated preparativeHPLC System or by column chromatography or thin layer chromatography toprovide the oxoacetylpiperazine derivative of formula QC(O)C(O)TC(O)A.

[0393] Biology

[0394] In Tables 7-9 and hereafter, the following definitions apply.

[0395] “μM” means micromolar;

[0396] “ml” means milliliter;

[0397] “μl” means microliter;

[0398] “mg” means milligram;

[0399] The materials and experimental procedures used to obtain theresults for representative compounds of Formula I reported in Tables 7-9are described below.

[0400] Cells:

[0401] Virus production—Human embryonic Kidney cell line, 293,propagated in Dulbecco's Modified Eagle Medium (Life Technologies,Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St.Louis, Mo.).

[0402] Virus infection—Human epithelial cell line, HeLa, expressing theHIV-1 receptors CD4 and CCR5 was propagated in Dulbecco's Modified EagleMedium (Life Technologies, Gaithersburg, Md.) containing 10% fetalBovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented with 0.2mg/ml Geneticin (Life Technologies, Gaithersburg, Md.) and 0.4 mg/mlZeocin (Invitrogen, Carlsbad, Calif.).

[0403] Virus-Single-round infectious reporter virus was produced byco-transfecting human embryonic Kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences (Chen et al, Ref. 41). Transfections were performedusing lipofectAMINE PLUS reagent as described by the manufacturer (LifeTechnologies, Gaithersburg, Md.).

[0404] Experiment

[0405] 1. Compound was added to HeLa CD4 CCR5 cells plated in 96 wellplates at a cell density of 5×10⁴ cells per well in 100 μl Dulbecco'sModified Eagle Medium containing 10% fetal Bovine serum at aconcentration of <20 μM.

[0406] 2. 100 μl of single-round infectious reporter virus in Dulbecco'sModified Eagle Medium was then added to the plated cells and compound atan approximate multiplicity of infection (MOI) of 0.01, resulting in afinal volume of 200 μl per well and a final compound concentration of<10 μM.

[0407] 3. Samples were harvested 72 hours after infection.

[0408] 4. Viral infection was monitored by measuring luciferaseexpression from viral DNA in the infected cells using a luciferasereporter gene assay kit (Roche Molecular Biochemicals, Indianapolis,Ind.). Infected cell supernatants were removed and 50 μl of Dulbecco'sModified Eagle Medium (without phenol red) and 50 μl of luciferase assayreagent reconstituted as described by the manufacturer (Roche MolecularBiochemicals, Indianapolis, Ind.) was added per well. Luciferaseactivity was then quantified by measuring luminescence using a Wallacmicrobeta scintillation counter.

[0409] 5. An EC₅₀ provides a method for comparing the antiviral potencyof the compounds of this invention. The effective concentration forfifty percent inhibition (EC₅₀) was calculated with the Microsoft ExcelXlfit curve fitting software. For each compound, curves were generatedfrom percent inhibition calculated at 10 different concentrations byusing a four parameter logistic model (model 205). The EC₅₀ dataobtained is shown below in Tables 7-9. In Tables 7-9, compounds with anEC₅₀ of greater than 5 μM are designated as Group C; compounds with anEC₅₀ of 1 μM to 5 μM are designated Group B; compounds with an EC₅₀ ofless than 1 μM are designated as Group A; and compounds with a potencyof greater than 0.5 μM which were not evaluated at higher doses todetermine the EC₅₀ value are designated Group D. TABLE 7

W, Example m, n, p, R⁹, # Q R^(9′) T Group 1

m = 1, n = 0 p = 1

A 2

m = 1, n = 0 p = 1

A 3

m = 1, n = 0 p = 1

A 4

m = 1, n = 0 p = 1

A 5

m = 1, n = 0 p = 1

A 6

m = 1, n = 0 p = 1

A 7

m = 1, n = 0 p = 1

A 8

m = 1, n = 0 p = 1

A 9

m = 1, n = 0 p = 1

A 11

m = 1, n = 0 p = 1

A 12

m = 1, n = 0 p = 1

A 13

m = 1, n = 0 p = 1

A 14

m = 1, n = 0 p = 1

B 15

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 16

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 17

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 18

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 19

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 20

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

B 21

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 22

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

B 23

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

B 24

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

B 25

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 26

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 27

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 28

m = 1, n = 0 p = 1

D 29

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 30

W = NH, m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

D 31

W = NH, m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

D 32

W = NH, m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

A 33

m = 1, n = 0 p = 1

A 34

m = 1, n = 0 p = 1

A 35

m = 1, n = 0 p = 1

A 36

m = 1, n = 0 p = 1

A 37

m = 1, n = 0 p = 1

A 38

m = 1, n = 0 p = 1

A 39

m = 1, n = 0 p = 1

B 40

m = 1, n = 0 p = 1 R⁹ = —CN, R^(9′) = —H

C 41

m = 1, n = 0 p = 1

B 42

m = 1, n = 0 p = 1

A

[0410] TABLE 8

Example # BZ R¹⁵ Group 42

H B 43

Me B 44

H B 45

Me B 46

Me B 47

Me B 48

(R)-Me B 49

H A 50

(R)-Me A 51

H A 52

(R)-Me A 53

(R)-Me B 54

(R)-Me A 55

(R)-Me A

[0411] TABLE 9

Example # BZ R¹⁵ Group 56

H A 57

H A 58

Me A 59

(R)-Me A

[0412] The compounds of the present invention may be administeredorally, parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand diluents.

[0413] Thus, in accordance with the present invention, there is furtherprovided a method of treating and a pharmaceutical composition fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the present invention.

[0414] The pharmaceutical composition may be in the form of orallyadministrable suspensions or tablets; nasal sprays, sterile injectablepreparations, for example, as sterile injectable aqueous or oleagenoussuspensions or suppositories.

[0415] When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents, and lubricants known in the art.

[0416] The injectable solutions or suspensions may be formulatedaccording to known art, using suitable non-toxic, parenterallyacceptable diluents or solvents, such as mannitol, 1,3-butanediol,water, Ringer's solution or isotonic sodium chloride solution, orsuitable dispersing or wetting and suspending agents, such as sterile,bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0417] The compounds of this invention can be administered orally tohumans in a dosage range of 1 to 100 mg/kg body weight in divided doses.One preferred dosage range is 1 to 10 mg/kg body weight orally individed doses. Another preferred dosage range is 1 to 20 mg/kg bodyweight in divided doses. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

What is claimed is:
 1. A compound of Formula I, includingpharmaceutically acceptable salts thereof,

wherein: Q is

A is selected from the group consisting of C₁₋₆alkoxy, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, and heteroaryl; wherein said heteroaryl may bemonocyclic or bicyclic and may be comprised of three to eleven atomsselected from the group consisting of C, N, NR⁹, O, and S, and whereineach ring of said phenyl and heteroaryl is optionally substituted withone to five same or different substituents selected from the groupconsisting of R¹⁹-R²³; W is O or —NH; T is

Z¹ is CR¹ or N; Z² is CR² or N; Z³ is CR³ or N; Z⁴ is CR⁴ or N; Z⁵ isCR⁵ or N; Z⁶ is CR⁶ or N; Z⁷ is CR⁷ or N; Z⁸ is CR⁸ or N; R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected from the groupconsisting of a bond, hydrogen, halogen, cyano, nitro, X′R²⁴, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₄₋₇cycloalkenyl, C₂₋₆alkynyl, aryl,heteroaryl, heteroalicyclic, C(O)NR²⁸R²⁹, COR²⁵ and CO₂R²⁵; wherein saidC₁₋₆alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₄₋₇cycloalkenyl, C₂₋₆alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to nine same or different halogens or from one to five same ordifferent substituents selected from the substituents comprising groupF; m, n, and p are each independently 0, 1, or 2 provided that the sumof m, n, and p must equal 1 or 2; F is selected from the groupconsisting of C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy, cyano, halogen, benzyl,N-amido, NR³⁰R³¹, C₁₋₆alkylC(O)NR³⁰R³¹, C(O)NR³⁰R³¹, COOR³² andC₁₋₆alkylCOOR³²; R⁹ and R^(9′) are each independently selected from thegroup consisting of hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, cyano, andfluoro; or R⁹ and R^(9′) taken together with the carbon atom to whichthey are attached form —C═O, C═S, C═NOR¹⁰, —C═NH, or a 3 or 4 memberedring which may contain up to 1 heteroatom chosen from O, N, S; R¹⁰ ishydrogen or C₁₋₆alkyl; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ areeach independently selected from the group consisting of hydrogen, CH₂Fand C₁₋₃alkyl; or one of R¹¹ and R¹², R¹³ and R¹⁴, R¹⁵ and R¹⁶ or R¹⁷and R¹⁸ taken together with the carbon atom to which they are attachedmay form —C═O; X′ is selected from the group consisting of NR¹⁰, O, andS; R¹⁹, R²⁰, R²¹, R²², and R²³ are each independently selected from thegroup consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,halogen, cyano, X′R²⁶, trifluoromethyl, and trifluoromethoxy, whereineach of said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl are optionallysubstituted with one to three same or different substituents selectedfrom halogen and C₁₋₆alkyl; R²⁴ is hydrogen or C₁₋₆alkyl; R²⁵ isselected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl and heteroaryl; R²⁶ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, trifluoromethyl andC(O)R²⁷; R²⁷ is selected from the group consisting of C₁₋₆alkyl, NH₂ and—NHC₁₋₃alkyl; R²⁸ and R²⁹ are each independently selected from the groupconsisting of hydrogen, SO₂C₁₋₆alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl,heteroaryl, and heteroalicyclic wherein said C₁₋₆alkyl, C₃₋₇cycloalkyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to nine same or different halogens or C₁₋₆alkyl groups; R³⁰ and R³¹are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, wherein said C₁₋₆alkyl, C₃₋₇cycloalkyl,and aryl are optionally substituted with one to nine same or differenthalogens; R³² is selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₇cycloalkyl; provided that at any given time only oneof the members selected from the group consisting of R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and R⁸ is a bond, and further provided that said bond is thepoint of attachment to the adjacent carbon atom in the compound ofFormula I.
 2. A compound of claim 1, including pharmaceuticallyacceptable salts thereof, wherein: T is

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each independentlyhydrogen or methyl; W is O; and A is phenyl or heteroaryl wherein saidheteroaryl is monocyclic and may be comprised of 5 to 6 atoms selectedfrom the group consisting of C, N, NR⁹, O. and S, and wherein each ringof said phenyl and heteroaryl is optionally substituted with one bromo,fluoro, or methyl group,
 3. A compound of claim 2, includingpharmaceutically acceptable salts thereof, wherein: R⁹ and R^(9′) areeach independently hydrogen or cyano.
 4. A compound of claim 2,including pharmaceutically acceptable salts thereof, wherein: m is 1; nis 0; and p is
 1. 5. A compound of claim 4, including pharmaceuticallyacceptable salts thereof, wherein: Q is:

and R is a bond for point of attachment.
 6. A compound of claim 5,including pharmaceutically acceptable salts thereof, wherein: Q is

and R is a bond for point of attachment.
 7. A compound of claim 5,including pharmaceutically acceptable salts thereof, wherein: Q is

and R⁶ is a bond for point of attachment.
 8. A compound of claim 4,including pharmaceutically acceptable salts thereof, wherein: Q is:

and R⁶is a bond for point of attachment.
 9. A compound of claim 4,including pharmaceutically acceptable salts thereof, wherein: one of Z₁through Z₈ is N.
 10. A compound of claim 4, including pharmaceuticallyacceptable salts thereof, wherein: two of Z₁ through Z₈ is N.
 11. Apharmaceutical composition which comprises an antiviral effective amountof a compound of Formula I, including pharmaceutically acceptable saltsthereof, as claimed in any of claims 1-10, and one or morepharmaceutically acceptable carriers, excipients or diluents.
 12. Thepharmaceutical composition of claim 11, useful for treating infection byHIV, which additionally comprises an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: (a) an AIDSantiviral agent; (b) an anti-infective agent; (c) an immunomodulator;and (d) HIV entry inhibitors.
 13. A method for treating a mammalinfected with a virus comprising administering to said mammal anantiviral effective amount of a compound of Formula I, includingpharmaceutically acceptable salts thereof, as claimed in any of claims1-10, and one or more pharmaceutically acceptable carriers, excipientsor diluents.
 14. The method of claim 13, comprising administering tosaid mammal an antiviral effective amount of a compound of Formula I incombination with an antiviral effective amount of an AIDS treatmentagent selected from the group consisting of: an AIDS antiviral agent; ananti-infective agent; an immunomodulator; and an HIV entry inhibitor.15. The method of claim 13 wherein said virus is HIV.
 16. The method ofclaim 14 wherein said virus is HIV.